James Watson: Antioxidants are a cancer's best friend. Or they're not
Last week, James Watson, of the famed Nobel Laureate duo Watson and Crick, published a lengthy and compelling cancer manifesto in Open Biology. Its title: Oxidants, antioxidants and the current incurability of metatastic cancers
Taking today’s widely-held consensus on the benefits of antioxidants, he turns conventional wisdom on its head with an observation so glaringly obvious that’s I’m genuinely shocked I haven’t heard it bandied about prior. Of course, true to form, Watson’s positions are not without controversy. But, before we delve into them, a little background is required.
I’m going to let you in on a little secret. There’s no cure for cancer. There could never be, and will never be a cure for cancer. See, cancer isn’t a thing. It’s not a fightable foe, like a bacterial infection or George Foreman. It’s not an simple environmental agent that you can remove from your surroundings like Agent Orange or Aunt Tilda. The reason you cannot cure cancer is because cancer isn’t one disease. Or a hundred diseases. Or a thousand diseases.
Cancer is millions of diseases. Cancer can become other diseases within the same cancer patient. Cancer is the varied and seemingly innumerable ways in which the abnormal cells in the human body can exhibit uncontrolled growth. And it’s changing all the time.
My labmate and I used to joke that our molecular biology course could have been renamed Cancerpalooza without a single change in syllabus. That’s because, when you get down to it, cancer happens when the molecular machinery that turns DNA into stuff gets fucked up.
A single fuck up won’t give you cancer. Which is good, as fuck ups happen all the time. Your body is adept at finding shit that doesn’t work and throwing lysosomes at it, as well as other techniques to seek and destroy potential issues, such as: DNA and RNA transcripts that look weird, proteins that act like maniacs and refuse to do their jobs correctly, proteins that over-aggressively do their job, transcription factors that act like certifiable lunatics, and so on and so forth.
Typically, you need at least two defiant molecular problem children for cancer to get a leg up and have a fighting chance at breaking some shit. Also, these fuck ups need to be survivable for the cell (cell death is another handy way to avoid the big C - more on this later). So, what kind of cellular mistakes are we talking about?
So glad you asked. In order to understand cancer, it helps if you try to think of it like a nefarious thing that wants to exploit cellular machinery. (Of course, cancer is nothing more than a random event in the midst of our chaotic, random lives, but it helps to conceptualize cancer’s methodology if you make it an evil, mustachioed hijacker or a greased-up Danny Devito in a cheap, pinstripe suit, trying to sell you back the shoes it stole from you yesterday. And succeeding.)
Cancer is the ultimate opportunist. Where you or I would see a cluster of genetic mutations, cancer sees a way to turn off programmed cell death, churn out proteins at an accelerated rate, and say, build a hefty vascular system for the tumor that it is delighted to be growing.
Remember that dispatch in which I listed many of the ways that the central dogma of molecular biology - DNA to RNA to protein - could get borked? Those mistakes set the stage for cancer to steal the show. Overly sticky transcription factors staying bound to the promoter, causing RNA polymerase to keep hopping on and making RNA transcripts? Cancer would love that. Introns being left in the mature RNA transcript? Hey, might turn out a protein that helps the cell do something naughty. Cancer would be all about that. Something unusual happens that changes the methylation of DNA, and thus changes how a cluster of genes is expressed? Cancer, cancer, cancer.
The cancer cell is also a rule breaker. It’s not enough to just be abnormal: the weird lump of goo in the corner of the party isn’t going to get the cops called. No, that lump of goo is going to have to stir up some shit and punch a few fratboys if it’s going to earn the moniker of a true troublemaker.
To hit the cancer jackpot, a cell needs mutations that give it the capacity for uncontrolled growth. So, anything that messes with the machinery that oversees apoptosis, that is, scheduled cell death, is a major plus in Cancerland. Avoiding its programmed lifespan and finding ways around the limits that on how many times its DNA can be copied is a hallmark of malignancies. Unregulated cell growth is the differentiates between a malignant versus benign tumor, the latter of which cannot grow uncontrollably, invade neighboring tissue, or spread throughout the body (all things that cancer can do). Also, anything the cell can do to circumvent the mechanisms in place to find and repair damaged DNA is good for cancer.
For example, there’s Myc. Myc is a transcription factor, a gene transcription activator protein that binds the promoter region of DNA and acts as kind of a molecular handle for RNA polymerase.
Think of transcription factors as someone pushing an elevator button in a skyscraper. Mr. Transcription Factor pushes an elevator button and the elevator (RNA polymerase) knows which floor he wants and goes to that location. Myc then, is a child that pushes as many elevator buttons as it can, just wiping their chubby little kid hands up and down the light-up button panel. Myc turns simultaneously cranks up the synthesis of over a thousand different proteins that are required to move cells through the cell cycle. As remarked in Watson’s paper, “Although precisely how this almost 400-amino acid long polypeptide works at the molecular level remains to be worked out, it seems to play a unique role that cannot be handled by any other class of transcription factors.” Understandably, then, Myc plays a huge role in many cancers, including small cell lung cancers and receptor negative and ductal breast cancers.
Which brings me back to Watson’s sprawling cancer manifesto. Watson covers an impressive amount of ground, providing a well-written and concise account of cancer research, to date. And while it would warm my heart to pour through the paper with you, sentence by sentence, turning a masterful piece of scientific literature into an easily understood and contextualized piece of journalism, the length and scope of such a dispatch would be alarmingly prohibitive. So, in line with the earnest clarity with which I enjoy sharing science news with you, let’s take a closer look at the media dog whistle buried in the dense meat of Watson’s paper: the relationship between oxidants, antioxidants, and cancer.
Maybe you’ve already seen the headlines, “Antioxidants cause cancer?!” and silently began to panic over your vitamin C fortified juice box. Take a deep breath and fill your nostrils with the earthy aroma of biological complexity: Nothing is ever, ever that simple.
Watson’s novel hypothesis involves the role of oxidants and antioxidants in late-stage (terminal) metastatic cancer. For any of Watson’s work to make sense, we have to understand oxidative stress and the role it plays in cancer. For more on this, I spoke to a cancer researcher, who for reasons related to the sensitive nature of his research, prefers to remain nameless.
“Oxidative stress is the term given for when hydroxyl molecules have the ability to bind and interact with molecules drastically altering the function or causing damage by degradation.” The molecules, or species that do this are referred to as reactive oxygen species, or ROS.
“ROS are broken down from hydrogen peroxide by normal cellular activities – amusingly that the simple act of thinking can lead to ROS activation in neural cells – which then goes on to attack DNA causing breakages.”
Is oxidative stress enough to cause cancer, in and of itself? In short, no. As it was helpfully pointed out to me, were this the case we’d be riddled with cancer while we were still in utero.
In science speak: “It does, however, act as a signal for P53 activation which will move along the DNA transcribing p21 gene as it goes, which will then move to becoming a protein and hold the cell in suspended animation through a cascade of other events.”
In English: P53 is incredibly important because it decides whether the cell should undergo repairs or be destroyed.
Okay, then, so if oxidative stress bad … antioxidants good, right?
Well, when you're making copies of your DNA, yes: Antioxidants are good. “When DNA replicates during cellular division or in the transcription of genes, its telomeres - the ends of chromosomes that protect the genome from degradation - shorten, thus resulting in parts of genes missing or being rearranged.”
Telomeres also reduce ROS damage to DNA. If telomeres are shortened, cells age; if they are kept long, aging is delayed. Cancer cells have high telomerase activity, and thus, their cellular aging mechanisms are all virtually nonexistent.
So if you are not a cancer cell and you want to protect your DNA during replication or transcription, having antioxidants around is a great way to mop up excess oxygen species and prevent damage to your precious genetic makeup.
But wait. What if you are cancer? Wouldn’t antioxidants protect you too?
Ding ding ding ding ding!
Welcome to the controversial and intensely interesting part of Watson’s paper. Basically, he’s saying that perhaps it’s a terrible idea to be pumping cancer patients full of antioxidants while we are trying to kill their cells. Antioxidants mop up damaging ROS, which is great when you are exposed to too many damaging things and need to protect your cells. But what about when your cells have hijacked their molecular machinery and are flattly refusing senescence? Wouldn’t a swarm of anti-anti-oxidants perhaps be a good idea?
ROS are maddening. On the one hand, they are lauded for their ability to induce apoptosis, a way for highly stressed or damaged cells to off themselves. On the other, Watson notes, they are well understood for “their ability to irreversibly damage key proteins and nucleic acid molecules [e.g., DNA and RNA].”
Maybe for now, as my source put it, we should advise people that “blueberries should be eaten because they taste good, not because they will lead to less cancer.”